Establishing Clinically Meaningful Change on Outcome Assessments Frequently Used in Trials of Mild Cognitive Impairment Due to Alzheimer's Disease.

BACKGROUND: Consensus is lacking on what constitutes a meaningful score change for individual patients on clinical outcome assessments (COAs) that are commonly used in clinical trials of Alzheimer's disease. Such thresholds are one important approach to help contextualize trial results and demonstrate meaningful treatment benefit. OBJECTIVES: To estimate meaningful within-patient change thresholds for the Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog), and the Mini-Mental State Examination (MMSE) among participants with mild cognitive impairment (MCI). DESIGN: Retrospective anchor- and distribution-based analyses of data from the ADC-008 (NCT00000173) study were used to estimate thresholds for meaningful within-patient change on the target measures. SETTING: Analyses were conducted using data from ADC-008 a Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study among participants with the amnestic subtype of MCI, which was conducted by the Alzheimer's Disease Cooperative Study (ADCS) between March 1999 and January 2004 in the United States and Canada. PARTICIPANTS: Analyses were based on 769 eligible participants who completed the baseline assessment from 69 ADCS sites in the United States and Canada. MEASUREMENTS: The target outcome measures for this analysis included the CDR-SB, the ADAS-Cog, and the MMSE. The anchor measures for this analysis included the Global Deterioration Scale and the MCI-Clinical Global Impression of Change. RESULTS: Focusing on the 12-month time point, within-patient increases of 1-2.5 points in the CDR-SB and increases of 2-5 points on the 11-item ADAS-Cog and 13-item ADAS-Cog, on average, reflect minimal-to-moderate levels of deterioration, respectively. CONCLUSIONS: These thresholds may be useful to aid the interpretation of Alzheimer's disease clinical trial data by illustrating meaningful within-patient progression over the course of a clinical trial via supplementary progressor analyses, which may in turn be informative for treatment decisions. Estimates generated via these methods are specifically intended to evaluate within-patient change and are not intended to assess the magnitude and meaningfulness of differences between group-level changes over time.

Occurrence of Salmonella enterica in grey-headed flying foxes from New South Wales.

Salmonella enterica and Campylobacter jejuni are significant foodborne zoonotic pathogens causing gastroenteritis in humans. Domestic animals are commonly implicated as reservoirs of S. enterica and C. jejuni, but both are also detected in wild animals. Salmonella enterica serovar Typhimurium is the most common cause of human salmonellosis in Australia; however, Salmonella enterica serovar Wangata is associated with sporadic human outbreaks in New South Wales and wild animals may be a potential reservoir. To determine if wild grey-headed flying foxes (GHFF; Pteropus poliocephalus) are reservoirs of Salmonella and Campylobacter, faecal samples were collected from three GHFF colonies in New South Wales and cultured for the presence of Salmonella and Campylobacter. One Salmonella isolate was cultured from 254 GHFF faecal samples (0.39%). Whole genome sequencing was used to genetically characterise the Salmonella isolate and perform phylogenetic analysis. The GHFF isolate was determined to be Salmonella Typhimurium ST19. The GHFF isolate carried a virulence plasmid and other virulence factors, but did not exhibit antimicrobial resistance. Phylogenetic analysis determined that the GHFF isolate was most closely related to a cluster of six isolates: four from human salmonellosis cases in Queensland and two from Australian livestock. Neither Campylobacter nor Salmonella Wangata were cultured from the 254 GHFF faecal samples. This study concluded that wild GHFF in New South Wales are not major reservoirs for Salmonella, and the zoonotic risks associated with S. enterica carriage by urban GHFF are low for the general public.

Psychometric Properties of the Clinical Dementia Rating - Sum of Boxes and Other Cognitive and Functional Outcomes in a Prodromal Alzheimer's Disease Population.

BACKGROUND: The Clinical Dementia Rating-Sum of Boxes (CDR-SB) has been proposed as a primary outcome for use in prodromal AD trials. However, the psychometric properties of this, and of other commonly used measures, have not been well-established in this patient population. OBJECTIVE: To describe the psychometric properties of commonly used efficacy measures in a clinical trial of prodromal AD. SETTING: Data were gathered as part of a two-year clinical trial. PARTICIPANTS: Patients had biomarker confirmed prodromal AD. MEASUREMENTS: Clinical Dementia Rating (CDR), Functional Activities Questionnaire (FAQ), Alzheimer's Disease Assessment Scale - Cognition Subscale 11 and 13 (ADAS-Cog), Mini Mental State Exam (MMSE), and Free and Cued Selective Reminding Test (FCSRT-IR [words]). Assessments were conducted at least every 24 weeks. RESULTS: For the CDR-SB, test-retest reliability was good (intra-class correlation coefficient [ICC]=0.83); internal consistency was 0.65 at baseline but above 0.8 at later assessments. Relationships between the CDR-SB and other measures were as expected (higher correlations with more closely related constructs), and the CDR-SB differentiated between patients with different severities of dementia (-2.9 points difference between CDR-Global Score 0.5 and 1, P<.0001). Floor and ceiling effects on the CDR-SB total score were minimal; however, at baseline there were ceiling effects in the personal care domain. Further detail is provided on the psychometric properties of ADAS-Cog, MMSE, FCSRT-IR and FAQ in this population. CONCLUSION: The psychometric properties of the CDR-SB are adequate in prodromal AD and continued use is warranted in clinical trials. However, there remains scope for improvement in the assessment of functional constructs and development of novel measures should continue.

Prevalence and symptomatology of depression in older people living in institutions in England and Wales.

BACKGROUND: Epidemiological studies have shown that depression is common in institutional settings. However, the symptomatology of depression in this group has not been compared to those living in the community. AIMS: To estimate the prevalence of depression and depressive symptomatology in participants living in institutions and compare these to people living in other settings. METHOD: The Medical Research Council Cognitive Function and Ageing Study (MRC CFAS) is a population-based cohort comprising 13,004 individuals aged 65 and above, from five sites across England and Wales. Following screening, a stratified random sub-sample of 2,640 participants received the Geriatric Mental State (GMS) examination of whom 340 resided in institutions. Diagnoses of depression were made using the Automated Geriatric Examination for Computer-assisted Taxonomy system (AGECAT). RESULTS: The prevalence of depression in those living in institutions was 27.1% (95% CI 17.8-36.3) compared to 9.3% (95% CI 7.8-10.9) in those living at home. Symptoms relating to depressed mood, severity of illness (e.g. wishing to be dead, future looking bleak) and some non-specific symptoms were more common in those living in residential homes. Depression was significantly associated with younger age (P = 0.002) and high functional disability (P = 0.009) in those living in institutions. CONCLUSIONS: Consistent with previous estimates, depression was highly prevalent in institutions, particularly in younger individuals with severe functional impairment. Those in institutions report considerably more symptoms of depression. Finding interventions which address these symptoms might improve quality of life for people in institutions, irrespective of formal diagnoses.

The absence of rhamnose in human urine following the ingestion of gum karaya (Sterculia).

Urinary rhamnose estimations following ingestion of gum karaya were requested by the Scientific Committee for Food (EEC) in July 1983. Five male volunteers have therefore made 24-h urine collections prior to, and following, the ingestion of 10 g gum karaya for 15 days, an intake ten-fold greater than that approved in terms of the present temporary ADI (0-12 X 5 mg/kg b.w.). Paper chromatographic separations, with two solvent systems, were made on the fresh urine specimens and also after ten-fold enrichments of all urinary constituents. Standard aqueous solutions of rhamnose, and urine to which rhamnose had been added, showed the detection limit to be 0.2 microgram rhamnose. Independent examinations in two laboratories failed to detect rhamnose at this level in any of the urine specimens, Had 1% of the rhamnose present in 10 g gum karaya appeared in the 24-h urine specimens, it would have been detected. This confirms previous evidence that dietary gum karaya is neither digested nor degraded by enteric bacteria and is not absorbed to any significant extent in Man.